# Anxiolytic Effects and Abuse of BZ Receptor Ligands

> **NIH NIH R01** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $468,631

## Abstract

Although benzodiazepines (BZs) are considered to be among the safest prescription drugs in modern medicine,
their utility is constrained by a number of side effects, including the liability for abuse, and recent epidemiological
research suggests BZ abuse is on the rise in the U.S. The overall goal of this application is to investigate the
extent to which GABAA receptor subtypes are differentially involved in self-administration vs. anxiolytic-like
effects of BZ ligands, with the goal of developing medications to treat BZ addiction. This renewal application
builds on our work from past project periods that has implicated unique roles for α1, α2, and α3 subunit-containing
GABAA receptors (α1GABAA, α2GABAA, α3GABAA receptors, respectively) in the anxiolytic-like effects and
abuse potential of BZs. The key findings from our work include: (1) compounds lacking efficacy at α1GABAA
receptors and relatively low efficacy at α2GABAA/α3GABAA receptors may have reduced abuse potential
compared with conventional BZs, but retain robust anxiolytic-like effects; and (2) antagonists that target
α1GABAA, α2GABAA, and α3GABAA receptors, but not α5GABAA receptors, can block the reinforcing effects of
BZs. In addition, we have obtained enough data and novel ligands to propose the development of
pharmacotherapies for BZ addiction, i.e., medication-assisted treatment. Nevertheless, significant knowledge
gaps remain before lead compounds can be selected and optimized. Using relevant nonhuman primate models,
our proposed studies specifically will evaluate the hypotheses that (1) the anxiolytic-like effects of BZs are
mediated by α2GABAA receptor subtypes; (2) intrinsic efficacy at α1GABAA receptor subtypes is a key
determinant of the reinforcing effectiveness of BZ-type ligands; and (3) different levels of intrinsic efficacy at
GABAA receptor subtypes determine the extent to which subtype-selective ligands alter the reinforcing effects of
abused BZs. Anxiolytic activity will be evaluated in rhesus monkeys using conflict procedures in which food-
maintained behavior is concurrently suppressed by response-produced presentations of an aversive stimulus.
Abuse potential will be assessed using behavioral economics and progressive-ratio schedules, in conjunction
with quantitative pharmacological analysis. Our approach to identifying receptor mechanisms and therapeutic
strategies may have a profound and long-lasting impact on not just the scientific field, but also the treatment-
provider community and, most importantly, the patients struggling with BZ addiction.

## Key facts

- **NIH application ID:** 9972401
- **Project number:** 2R01DA011792-22
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** JAMES K ROWLETT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $468,631
- **Award type:** 2
- **Project period:** 1998-06-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972401

## Citation

> US National Institutes of Health, RePORTER application 9972401, Anxiolytic Effects and Abuse of BZ Receptor Ligands (2R01DA011792-22). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9972401. Licensed CC0.

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